Abstract
Background/Objectives: COVID-19 severity is influenced by a complex interplay between host, viral, and environmental factors. Emerging evidence suggests that Neanderthal-derived genetic variants may influence the progression and severity of SARS-CoV-2 infection. This study aimed to evaluate the association between selected Neanderthal-derived variants and COVID-19 severity in the population of the Republic of Srpska, considering relevant clinical, sociodemographic, and lifestyle factors. Methods: This multicentric cross-sectional study included 402 participants, classified as healthy or SARS-CoV-2-positive individuals. A total of 378 COVID-19-positive participants were further stratified according to disease severity and hospitalization status. All individuals were genotyped for the Neanderthal-derived OAS3 rs1156361 (C/T) and LZTFL1 rs35044562 (A/G) variants. Detailed sociodemographic, clinical, and lifestyle data were also collected. Results: A higher frequency of the LZTFL1 rs35044562 AG genotype was observed among hospitalized patients compared with non-hospitalized individuals (36.8% vs. 20.9%; p = 0.005), while the AA genotype was more prevalent among non-hospitalized patients (77.3% vs. 63.2%, p = 0.015). Multivariable logistic analysis showed that carriers of the LZTFL1 AG genotype had a higher chance of hospitalization compared to AA carriers (adjusted OR = 1.372, 95% CI = 0.763-6.383, and p = 0.021). Hospitalized patients more frequently carried the combined CT (OAS3) and AG (LZTFL1) genotypes, supporting a potential synergistic effect. Several sociodemographic factors, including age, sex, education, employment, and urban residence, were also associated with COVID-19 severity, while no significant associations were observed in allele-based analyses. Conclusions:LZTFL1 gene polymorphisms may influence COVID-19 severity, with heterozygote-specific and combined risk effects observed. These preliminary findings are exploratory and require validation in larger cohorts, but may guide future studies and targeted interventions in high-risk groups.